Journal
EUROPEAN JOURNAL OF CLINICAL INVESTIGATION
Volume 52, Issue 6, Pages -Publisher
WILEY
DOI: 10.1111/eci.13769
Keywords
endothelial cell; extracellular vesicle; microvesicle; proteomics; T cells
Funding
- Swiss National Science Foundation [169194]
- Swiss Heart Foundation
- Zurich Heart house-Foundation of Cardiovascular Research
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The study revealed that CD4(+) T cells release a significant amount of microvesicles enriched with proteins related to immune responses, inflammation, and apoptosis upon receptor-mediated activation. These microvesicles disrupt microvascular endothelial function and barrier permeability, potentially contributing to tissue inflammation.
Background Microvesicles are vesicles shed by plasma membranes following cell activation and apoptosis. The role of lymphocyte-derived microvesicles in endothelial function remains poorly understood. Methods CD4(+) T cells isolated from peripheral blood of healthy human donors were stimulated using anti-CD3/anti-CD28-coated beads. Proteomic profiling of microvesicles was performed using linear discriminant analysis (LDA) from activated T cells (MV.Act) and nonactivated T cells (MV.NAct). In addition, data processing analysis was performed using MaxQUANT workflow. Differentially expressed proteins found in MV.Act or MV.NAct samples with identification frequency = 100%, which were selected by both LDA (p < .01) and MaxQUANT (p < .01) workflows, were defined as high-confidence differentially expressed proteins. Functional effects of MV.Act on human primary microvascular endothelial cells were analysed. Results T cells released large amounts of microvesicles upon stimulation. Proteomic profiling of microvesicles using LDA identified 2279 proteins (n = 2110 and n = 851 proteins in MV.Act and MV.NAct, respectively). Protein-protein interaction network models reconstructed from both differentially expressed proteins (n = 594; LDA p <= .01) and high-confidence differentially expressed proteins (n = 98; p <= .01) revealed that MV.Act were enriched with proteins related to immune responses, protein translation, cytoskeleton organisation and TNF alpha-induced apoptosis. For instance, MV.Act were highly enriched with IFN-gamma, a key proinflammatory pathway related to effector CD4(+) T cells. Endothelial cell incubation with MV.Act induced superoxide generation, apoptosis, endothelial wound healing impairment and endothelial monolayer barrier disruption. Conclusions T cell receptor-mediated activation of CD4(+) T cells stimulates the release of microvesicles enriched with proteins involved in immune responses, inflammation and apoptosis. T cell-derived microvesicles alter microvascular endothelial function and barrier permeability, potentially promoting tissue inflammation.
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